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Thiazolo[4,5‐ d ]pyrimidines. Part I. synthesis and anti‐human cytomegalovirus (HCMV) activity in vitro of certain alkyl derivatives
Author(s) -
Lewis Arthur F.,
Revankar Ganapathi R.,
Fennewald Susan M.,
Rando Robert F.,
Huffman John H.
Publication year - 1995
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570320230
Subject(s) - chemistry , pyrimidine , alkylation , uracil , human cytomegalovirus , stereochemistry , alkyl , in vitro , guanine , organic chemistry , dna , nucleotide , biochemistry , catalysis , gene
Alkyl derivatives of the thiazolo[4,5‐ d ]pyrimidine congeners of guanine and uracil were prepared and assessed for in vitro activity against human cytomegalovirus (HCMV). The finding that the 3‐pentyl 1b and 3‐hexyl 1c derivatives of 5‐aminothiazolo[4,5‐ d ]pyrimidine‐2,7(3 H ,6 H )‐dione (1e) had potent in vitro anti‐HCMV activity prompted a broader study of alkyl derivatives in this ring system. A series of 3‐alkyl derivatives of 1e , viz. 1f‐w , were prepared by direct alkylation of the sodium salt of 1e and by subsequent modifications, 2a‐d. For comparison with 1c , 5‐amino‐2‐hexylaminothiazolo[4,5‐ d ]pyrimidin‐7(6 H )‐one (4) was prepared and studied. The 3‐(2‐alkenyl) derivatives of 1e were found to be the more active antiviral agents with the Z isomer of 5‐amino‐3‐(2‐penten‐1‐yl)thiazolo[4,5‐ d ]pyrimidine‐2,7(3 H ,6 H )‐dione (1f) having the better therapeutic index. Analogous 4‐(2‐alkenyl) derivatives of 2‐aminothiazolo[4,5‐ d ]pyrimidine‐5,7(4 H ,6 H )‐dione 6a and 6b were also prepared but were found to have poor therapeutic indices. Single crystal X‐ray diffraction analysis was used to unequivocally establish the structure of 1f.